This proposal for the NIH Director's Early Independence Award is designed to realize the promise of genomics for improving health of all people by achieving a more complete understanding of the global architecture of human genomic diversity. This will be achieved by characterization global genomic diversity, including sequence and structural variation, in the context of the demographic history of human populations. To achieve this objected we propose three specific aims: (1) improve description of human demographic history and global diversity, (2) assess impact of demographic history on functional variation and inferences of archaic contributions to human variation and (3) develop methods to genotype genomic structural variation using short-read sequencing. The proposed research will provide essential information concerning the global prevalence and characteristics of under-ascertained variant types, clarify important characteristics of human population history, and define the lasting effects of this history on variation that is relevant for extant populations, including admixed or cosmopolitan populations whose genomes include segments from diverse continental ancestries. Understanding these global patterns of diversity, including sequence and structural variants, will be critical for proper execution and interpretation of studies designed to elucidate the genetic basis for disease susceptibility in diverse human populations. PUBLIC HEALTH RELEVANCE: Some genetic variants play an important role in altering susceptibility to human disease. These variants include both changes to the sequence and to the structure of genomes, and are known to vary across global populations. A more comprehensive understanding the nature of global patterns of genetic diversity will aid researchers in the identification of genetic variants relevant to disease risk in populations today.